DESCRIPTION: (adapted verbatim from the investigator's abstract) Metastasis is one of the most formidable clinical problems. The recent development of innovative multimodality therapy for patients with localized pancreatic adenocarcinoma has improved local disease control, yet resulted in only a modest improvement in overall survival due to the development of metastases. The current treatments for metastatic pancreatic adenocarcinoma are largely ineffective and pancreatic adenocarcinoma has become the fifth leading cause of adult cancer mortality. Therefore, future therapeutic strategies must be based on greater understanding of the molecular basis of metastasis. The goals of the research are to determine the roles of RelA in pancreatic metastasis and test inhibitors for RelA in repressing metastasis in an experimental model for pancreatic cancers. The signal transduction pathways for activation of RelA may represent a previously unexplored area for development of novel anti- cancer strategies. The Rel/NF-kBIkB transcription control complex is involved in embryonic development, lymphoid differentiation, cell adhesion, and apoptosis. Furthermore, the c-rel member of Rel/NF-kB transcription factor family was first identified as a cellular homologue of the v-rel oncogene, suggesting that other members of the Rel/NF-kB family are potentially oncogenes. However, the role of Rel/NF-kB in metastasis remains to be elucidated, and the relevant metastatic target genes that are regulated by Rel/NF-kB have yet to be identified. In the studies, they detected constitutively active RelA (p65 subunit of Rel/NF-kB) in 14 of 20 (70 percent) pancreatic adenocarcinomas but not in normal pancreas tissue. They also detected it in 7 of 11 (64 percent) human pancreatic tumor cell lines, which suggests that RelA may play a critical role in the development of pancreatic adenocarcinoma. Moreover, the preliminary results showed that activated RelA may promote metastasis by inducing uPA overexpression. They hypothesize that constitutively activated RelA plays a critical role in pancreatic metastasis by inducing the expression of downstream target genes and that the inhibition of RelA activity may suppress the metastatic potential. To test the hypotheses, they will specifically inhibit RelA by overexpressing the dominant negative IkBa (IkBaM), and determine whether (1) inhibition of RelA activation by IkBaM suppresses pancreatic cancer cell metastatic potential. (2) if uPA are the downstream target genes regulated by RelA in pancreatic cancer cells. (3) if the chemical inhibitors for RelA activation suppress or reduce metastatic potential. These studies may in turn lead to the development of specific inhibitors of Rel/NFkB that are more effective against pancreatic cancers metastasis.